title: Silencing of doublecortin-like (DCL) results in decreased mitochondrial activity and delayed neuroblastoma tumor growth.
abstract: Doublecortin-like (DCL) is a microtubule-binding protein crucial for neuroblastoma (NB) cell proliferation. We have investigated whether the anti-proliferative effect of DCL knockdown is linked to reduced mitochondrial activity. We found a delay in tumor development after DCL knockdown in vivo in doxycycline-inducible NB tumor xenografts. To understand the mechanisms underlying this tumor growth retardation we performed a series of in vitro experiments in NB cell lines. DCL colocalizes with mitochondria, interacts with the mitochondrial outer membrane protein OMP25/ SYNJ2BP and DCL knockdown results in decreased expression of genes involved in oxidative phosphorylation. Moreover, DCL knockdown decreases cytochrome c oxidase activity and ATP synthesis. We identified the C-terminal Serine/Proline-rich domain and the second microtubule-binding area as crucial DCL domains for the regulation of cytochrome c oxidase activity and ATP synthesis. Furthermore, DCL knockdown causes a significant reduction in the proliferation rate of NB cells under an energetic challenge induced by low glucose availability. Together with our previous studies, our results corroborate DCL as a key player in NB tumor growth in which DCL controls not only mitotic spindle formation and the stabilization of the microtubule cytoskeleton, but also regulates mitochondrial activity and energy availability, which makes DCL a promising molecular target for NB therapy.
authors.affiliation: Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Carla S
authors.initials: CS
authors.lastname: Verissimo
authors.forename: Rachel
authors.initials: R
authors.lastname: Elands
authors.forename: Sou
authors.initials: S
authors.lastname: Cheng
authors.forename: Dirk-Jan
authors.initials: DJ
authors.lastname: Saaltink
authors.forename: Judith P
authors.initials: JP
authors.lastname: ter Horst
authors.forename: Maria N
authors.initials: MN
authors.lastname: Alme
authors.forename: Chantal
authors.initials: C
authors.lastname: Pont
authors.forename: Bob
authors.initials: B
authors.lastname: van de Water
authors.forename: Bjarte
authors.initials: B
authors.lastname: Håvik
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Fitzsimons
authors.forename: Erno
authors.initials: E
authors.lastname: Vreugdenhil
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002522:Chlorocebus aethiops; D000089622:Doublecortin Domain Proteins; D015536:Down-Regulation / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D005260:Female; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D008941:Spindle Apparatus / Q000235:genetics / Q000378:metabolism
chemical_list: D000089622:Doublecortin Domain Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV